Pentobarbital (5-Ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione) is a barbiturate with the following structure

It is used as a sedative, a hypnotic for short term treatment of insomnia, a preanesthetic, and as an anticonvulsant in the emergency control of acute convulsive episodes. The drug can be administered intravenously or intramuscularly. A typical dose for pentobarbital sodium is 50 mg/mL. Common formulations of pentobarbital sodium injection include 40% propylene glycol and 10-15% alcohol. The recommended formulation pH range is 9.0-10.5.
Even within the recommended range of pH levels, the pH of pentobarbital formulations, like those of marketed formulations, can be problematic. On one hand, at a pH less than 9.0, pentobarbital precipitates. On the other, at high pH values greater than 9.0 that are typically necessary to keep pentobarbital in solution, the drug degrades over time via hydrolysis. Depending on their levels, the drug degradation products may affect drug potency or have toxicological effects. One primary degradation product involves a base-catalyzed ring opening of the ring in the pentobarbital molecule, as shown in the following reaction.
The degradation product (labeled “1” above and also called “Impurity 1” or “Related Compound 1”) accumulates to more than 1% of the active ingredient concentration before the end of three-year marketed drug formulation shelf life. Although the degradation is caused by high pH, even reducing the pH to 8.5 in a pentobarbital formulation containing 40% propylene glycol and 15% alcohol, failed to sufficiently stabilize pentobarbital. As a result, there is a need in the art to provide a pentobarbital formulation with greater stability and a lower impurity levels.